Antimetabolites can be used clinically for the treatment of diseases, such as, for example, bacterial and viral, as well as parasitical infections and in chemotherapies directed at tumors. Although antimetabolites, such as folate analogs and purine and pyrimidine analogs, have proven useful in the chemotherapy of cancer and in some cases, viral and other diseases, these therapeutic agents have significant side effects. As is the case with most chemotherapies directed at, for example, tumors, antimetabolites lack specificity for only tumor cells, and generally inhibit and kill, indiscriminately, all dividing cells, whether neoplastic or normal. Particularly vulnerable to the toxic effects of antimetabolites are the rapidly dividing progenitor cells of the hematopoietic system and of the gastrointestinal and oral mucosal epithelium. These serious side effects frequently compromise the health of the patient, and they limit the usable dosages of these agents, as a consequence of which tumor cells often evade destruction and develop drug resistance.
In addition to folate and purine and pyrimidine antimetabolites, many analogs of amino acids with good activity against various target cells, including tumors, viruses, bacteria, and protozoa (A. Meister, ed., Biochemistry of the Amino Acids, 2nd ed., Volume 1, 1965, 231-268), have been synthesized and investigated. However, amino acid analogs, like the aforementioned purine and pyrimidine and folate analogs, are not specific in their action and inhibit the proliferation of both normal and target cells, again leading to serious side effects, which reduce their utility and effectiveness.
Some proposals for ameliorating the toxic side effects of antimetabolites have been made and have been attempted in clinical studies. (J. D. Borsi et al, Rescue after Intermediate and High-dose Methotrexate: Background, Rationale, and Current Practice, Pediatric Hematology and Oncology, 7:347-363, 1990; M. Eleff et al. Analysis of “early” thymidine/inosine protection as an adjunct to methotrexate therapy, Cancer Research Rep., 69:867-874, 1985; G. K. Schwartz et al, A phase I trial of a modified, dose intensive FAMTX regimen (high dose 5-fluorouracil+doxorubicin+high dose methotrexate+leucovorin) with oral uridine rescue, Cancer, 78(9):1988-95, 1996). Because of many difficulties, none of these methods has been adopted into standard clinical practice, with the exception of “Leucovorin rescue.”